Transdermal therapeutic systems (TTS) for delivering active substances through the skin have been known for a long time. The topical application of drugs by way of active substance patch systems offers two main advantages. First, this form of administration produces first order release kinetics of the active substance, thereby enabling a constant level of active substance to be maintained in the body over a very long period. Second, the path of uptake through the skin avoids the gastrointestinal tract and also the first liver passage. As a result, selected drugs may be effectively administered in a low dose. This is particularly advantageous when the drug is desired to act locally while avoiding a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure sensitive adhesive. In the ready-to-apply product, a pressure sensitive adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing impermeable to the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (Kleben&Dichten, No. 42, 1998, p. 26 to 30).
A fundamental requirement of a TTS is very good adhesion to skin, which must be maintained over the entire duration of the intended dosing of active substance. A frequently observed side effect, however, is the appearance of skin irritations, which occur in particular when a TTS is applied for a relatively long period, or repeatedly, to the same body region. The principal cause of these irritations are the ingredients of the pressure sensitive adhesive matrix. Painful redetachment of the active substance patch following a prolonged period of wear is a further observation.
Repeated and long-lasting applications of pressure sensitive adhesive systems to the same regions of the human body are encountered above all in the area of ostomy care. In this utility, hydrocolloids have long been used with great success as pressure sensitive adhesives. They consist in principle of a hydrophobic, pressure sensitive adhesive polymer matrix based on synthetic rubbers, dispersed in which matrix there are insoluble hydrophilic fillers based on, for example, alginates, cellulose or pectins. In the development of hydrocolloids for ostomy care, however, the primary requirements are the adhesion properties to wet skin and the ability to absorb liquid.
As long ago as 1967, U.S. Pat. No. 3,339,546 described a hydrocolloid based on polyisobutylenes for use in the oral cavity. A great disadvantage of the early systems was the deficient integrity of the matrices, i.e., the dissolution and breakup of the pressure sensitive adhesive matrix on absorption of relatively large amounts of liquid.
Later developments therefore aimed to solve this problem, and a number of proposed solutions are described in the literature. U.S. Pat. No. 4,393,080, for example, describes a hydrocolloid system based on elastomers, which uses high molecular mass hydrophilic fillers which promote the cohesion of the system even when swollen. Further documents describe solutions by way of the crosslinking of the elastomer matrix, which may take place either physically or chemically.
Physical crosslinking, for example, may be effected by using phase separating block polymers based on poly(styrene-b-isoprene-b-styrene) (SIS), poly(styrene-b-isoprene-b-styrene) (SBS) or poly[styrene-b-(ethylene-stat.-butylene)-b-styrene] (SEBS). One of the first such systems is described, for example, in DE 28 22 535.
Chemical crosslinking may be effective, for example, by electron beam treatment or γ irradiation of the hydrocolloid matrix. A prerequisite for this is the presence in the pressure sensitive adhesive matrix of a sufficient number of reactive structural elements. This can be achieved, for example, as described in U.S. Pat. No. 4,477,325, by compounding with an ethylene-vinyl acetate copolymer.
Within the abovementioned inventions, although the technical problem of the cohesiveness of swollen hydrocolloids is described and solved, the problem of skin irritation as a result of repeated application is not addressed.
In contrast, WO 98/01167 A1 does deal with skin irritations that may occur. In this case, aloe vera extract is used in order to prevent inflammatory skin changes and infection in the context of ostomy care. The system described, however, merely comprises a low molecular mass polyisobutylene as the polymer framework, and so the above-described problem of the cohesiveness of the hydrocolloid matrix continues to exist. Moreover, the composition described uses tackifier resins, whose allergenic potential is known.
Information regarding the suitability of such a system for the controlled delivery of drugs is present neither in this nor in any other of the abovementioned documents.
Transdermal therapeutic systems are generally applied to healthy, intact skin. In this case in particular it is especially important that the intact skin is not irritated, let alone damaged, by a drug. Furthermore, sufficient cohesiveness is necessary in order to be able to remove the active substance patch without residue after the period of wear is at an end.
Polyisobutylenes have long been used as a framework substance in the compounding of pressure sensitive adhesives. Relative to other known elastomers, synthetic polymers based on isobutylene offer a number of advantages. Owing to their synthetic production, they are free from unwanted ingredients; owing to their complete saturation they are highly stable to oxidation; and their inherent tack can be adjusted depending on molecular weight.
For application to skin in particular, therefore, they are preferred over other elastomers. For example, the allergenic potential of natural rubber, deriving from its natural impurities, is well known. Other synthetic rubbers based on styrene and isoprene and/or butadiene are very oxidation sensitive, necessitating the complicated addition of additives. Their hydrogenated derivatives based on poly[styrene-b-(ethylene-stat-propylene)-b-styrene] (SEPS) or poly[styrene-b-(ethylene-stat-butylene)-b-styrene] (SEBS), although more stable to oxidation, nevertheless lack inherent tack. Because of this, they additionally require compounding with tackifier resins in order to be used as pressure sensitive adhesives, as is described, for example, in EP 0 651 635 B1. These resins are generally very poorly defined mixtures of substances, frequently based on rosin. Consequently, here again an allergenic potential can not be ruled out.
The use of polyisobutylenes for transdermal therapeutic systems is described in DE 3347 278 A1 and DE 33 47 277 A1. There, however, their use was always described in combination with either olefinic diene rubbers or tackifier resins, which again have the disadvantages described above. The use of amorphous poly-α-olefins as additives is also described, but without elucidating their effect on the overall system. The use of fillers is not mentioned in this description.
The use of PIB for transdermal systems without the addition of tackifier resins is described in U.S. Pat. No. 4,559,222. In that case, however, it is necessary to use very large amounts of mineral oil, the ratio of mineral oil to PIB in accordance with that invention being at least 1. Moreover, the system is restricted to active substances which are of moderate solubility in mineral oil. As a result, there is a further softening effect on the matrix. Fillers used comprise at least 6% by weight of colloidal silica. Regarding this ingredient, it is known that the antiadhesive properties of a release film are significantly disrupted by the use of silica.
WO 96/22083 A1 describes a system for the transdermal administration of nicotine which operates on the basis of polyisobutylene without the addition of mineral oil. In this case, however, the necessary tack of the adhesive composition is achieved through the use of tackifier resins. These have the abovementioned disadvantages with respect to skin compatibility. A plasticizing effect, which has an additional positive effect on the adhesive properties of the matrix, is achieved by way of the active substance which is soluble in the PIB matrix. This compounding principle, however, greatly restricts the selection of active substances which can be administered by way of this matrix.
A system for the transdermal administration of drugs, based on polyisobutylenes without the use either of tackifier resins or of mineral oil, is described by U.S. Pat. No. 5,508,038. The central component for achieving sufficient adhesive properties in this case too, however, is the active substance, which in accordance with that invention must be oily and of ready solubility in the nonpolar matrix. This constitutes a very severe restriction, ruling out the use of hyperemic active substances in this context. The system described is free from organic and inorganic fillers.
U.S. Pat. No. 5,508,038 is the only one of the cited publications to address the problem of skin irritation through the possible use of tackifier resins.
The use of amorphous poly-α-olefins in pressure sensitive adhesives in general is known in the literature. U.S. Pat. No. 4,186,258 is one of the first documents which designates the use of this class of substance in the field of hot-melt pressure sensitive adhesives. This document does not state a specific field of use.
U.S. Pat. No. 5,262,216 describes the use of these materials together with tackifier resins as hot-melt pressure sensitive adhesives, specifically for use on self-adhesive labels. Qualities of this class of polymer that are particularly praised here are the outstanding UV and aging resistance. There is no mention of their use on the human body.
WO 98/54268 A1, in contrast, specifically describes the use of amorphous poly-α-olefins for applications on human skin. Moreover, in this case amorphous poly-α-olefins are used in combination with fillers. However, the field of use described is specifically that of wound covering. In this application, a particular feature of amorphous poly-α-olefins is their outstanding radiation resistance, as a result of which, in accordance with that invention, it is possible to produce readily sterilizable woundcare products. Additionally, amorphous poly-α-olefins are used here in combination with tackifier resins. Overall, the aspect of reduced skin irritation is not mentioned. Moreover, WO 98/54268 A1 contains no indications that such a system is suitable for delivering drugs via the human skin. This document completely excludes the field of use of transdermal therapeutic systems.
The systems described to date for the transdermal administration of an active substance do not include organic fillers. However, these fillers in particular are responsible for the kindness to skin of the aforementioned pressure sensitive adhesives for ostomy care. By virtue of these fillers, moisture released by the skin during the period of wear of the patch can be absorbed very effectively. The resulting climate below the patch leads to a marked reduction in the incidence of skin maceration.
An invention of an active substance patch using water swellable fillers is described by EP 0 186019 A1. In that case, however, the positive influence of the organic filler on the release rate of the active substance is described. The filler content in accordance with that invention is limited to 30% by weight. The aspect of the reduction of skin irritation is not addressed. Moreover, the systems described are realized using tackifier resins.
As remarked above, the realization of pressure sensitive adhesive systems for the transdermal administration of active substances, based on polyisobutyl without either tackifier resins or mineral oil, is described only for those drugs which possess an oily consistency at room temperature and/or which are soluble in the matrix. Consequently, the use of hyperemic active substances, such as nonivamide, natural capsaicin, for example, is not possible on the basis of the known formulations, owing to the physical properties of these drugs. None of the tackifier resin free formulations described contains a hydrophilic filler.
It is an object of the present invention to develop, for the purpose of controlled delivery of a drug from the group of the hyperemic active substances, a hydrocolloid system which not only possesses excellent cohesiveness but is also composed of components which are particularly kind to the skin and can be realized without any need at all for skin irritant components such as tackifying resins, for example. Furthermore, a production process is planned which operates without any solvent whatsoever, and, furthermore, the abovementioned side effects of a pressure sensitive adhesive for transdermal systems—skin irritations and painful redetachments—are avoided, resulting in a significant increase in wear comfort for the patient. The object is therefore to provide a matrix system which is based on polyisobutylene and which can be realized in a solvent free production process without conventional tackifier resins and mineral oil.